US2904561A - 1-acylthio-4-pregnene-3, 20-diones - Google Patents

1-acylthio-4-pregnene-3, 20-diones Download PDF

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US2904561A
US2904561A US732454A US73245458A US2904561A US 2904561 A US2904561 A US 2904561A US 732454 A US732454 A US 732454A US 73245458 A US73245458 A US 73245458A US 2904561 A US2904561 A US 2904561A
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parts
volume
pregnene
dione
benzene
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US732454A
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Raymond M Dodson
Robert C Tweit
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GD Searle LLC
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GD Searle LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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  • compositions of this invention can be represented by the general structural formula wherein R is a (lower) alkanoyl radical, R is amember of the group of radicals consisting of acetyl, hydroxyacetyl and (lower) alkanoyloxyacetyl and X is a member whereinR" represents hydrogen or a lower alkyl radical, to a l,4-pregnadiene-3,20-dione which has the structural formula wherein R and X have the means as aforesaid.
  • the addition reaction to the 1,2-double bond proceeds fairly rapidly at elevated temperatures, such as those in excess of 50, and can be carried out optionally under the influence of ultraviolet light.
  • elevated temperatures such as those in excess of 50
  • ultraviolet light In carrying out the addition reaction with lower boiling thioalkanoic acids, such as thioacetic acid, it is convenient to conduct the reaction at the reflux temperature of the reaction mixture; whereas with higher boiling thioalkanoic acids it is convenient to conduct the reaction at a temperature of about 90-400". Heating periods of up to a few hours are sufficient to achieve substantial conversion to the desired reaction products.
  • the desired compound is obtained in a satisfactory state of purity by direct filtration of the cooled reaction mixture, preceded, where necessary, by removal of excess thioalkanoic acid.
  • reaction product can 2,904,561 Patented Sept. 15, 1959 be purified by chromatographic techniques using adsorbents such as silica gel followed by elution with mixtures of ethyl acetate and benzene.
  • adsorbents such as silica gel followed by elution with mixtures of ethyl acetate and benzene.
  • the compound desired is one having an esterified hydroxyl group at position 21, it is suitable to employ as starting material the corresponding 21-ester of a 2l-hydroxy-1,4-pregnadiene-3,ZO-dione; or alternatively, to carry out the addition reaction on the derivative having a free 21-hydroxyl group, and subsequently to complete the partial acylation effected by the thioalkanoic acid by adding pyridine and a lowar alkanoic acid anhydride of the same kind to the reaction mixture prior to the isolation of the product.
  • the final product desired is one having a free ZI-hydroxyl group
  • it can be obtained by the treatment of the corresponding Zl-hydroxy-l,4-pregnadiene-3,20- dione, suitably in an inert solvent, with only one molecular equivalent of the thioalkanoic acid. It can be obtained also by treating the free 21-hydroxy-1,4-pregnadiene derivative with an excess of the thioalkanoic acid, but under milder conditions, such as by the use of a shorter reaction time. The quantity of 21-ester which does form by the acylating action of the thioalkanoic acid is then removed by chromatography.
  • thioalkanoic acids to the 1,2-double bond of the starting materials employed in the practice of this invention proceeds under steric influences such that of the stereoisomers formed, one is obtained in predominant amount.
  • the isomer obtained in predominant amount has in each case been characterized herein as possessing the oc-COnfigulfltlOll of the l-acylthio group. This configuration has been designated in order to provide a more complete exposition of the present invention, and in order that the specification shall constitute a more useful contribution to the art.
  • the designated configuration of the l-acylthio group is based upon an analysis of the molecular rotation data presently appearing in the chemical literature, and is therefore not to 'be interpreted except in relation tothe state of the art presently known to organic chemists. It will be apparent that no part of the specification will be materially defective if it should be established later that the configuration is the opposite of that deducible from data presently available to workers in the field.
  • the compounds of the invention have useful pharmacological properties. They are hormonal agents of the luteoid and adrenocorticoid types, more specifically progestational agents and anti-inflammatory and neoglycogenet-ic agents of the cortisone type.
  • Example 1 A mixture of 2.0 parts by weight of l-dehydroprogesterone and 1 part by volume of thioacetic acid is heated and irradiated with ultraviolet light for one and one-half hours. To the mixture is added 10 parts by volume of benzene and the resulting solution concentrated under vacuum. The residue is stirred with ether and the solid which forms is collected and washed with a little ether to yield 1oz-acetylthioprogesterone; melting point 147.5- 149"; specific rotation +212.5 (chloroform); ultraviolet maximum at 241 m l with extinction coeflicient 16,300.
  • Example 2 A solution of 2.82 parts by weight of 21-acetoxy-17ahydroxy-l,4-pregnadiene-3,20-dione and 2 parts by volume of thioacetic acid is heated and irradiated with ultraviolet light. The reaction mixture is concentrated to onehalf volume in vacuo, cooled and diluted with ether. The solid precipitate which forms is collected and recrystallized from acetone to yield ZI-acetoxy-la-acetylthio- 17 a-hydroxy-4-pregnene-3,20-dione; melting point 202- 204 (dec.); specific rotation +149.5 (chloroform).
  • Example 3 A mixture of 0.65 part by weight of 17a,21-dihydroxy- 1,4-pregnadiene-3,11,20-trione ZI-ethylcarbonate and 0.6 part by volume of thioacetic acid is refluxed for 3 hours while irradiating with ultraviolet light. On standing overnight a solid residue forms. Part of the excess thioacetic acid is removed under vacuo and the solid residue is collected, washed with ether and crystallized twice from acetone to yield 1a-acetylthio-2l-ethylcarbonyldioxy-17ahydroxy-4-pregnene-3,l1,20-trione; melting point 202.5 205 (dec.); specific rotation +174 (chloroform).
  • Example 4 A mixture of 4.49 parts by weight of 21-acetoxy-l,4- pregnadiene-3,20-dione and 3 parts by volume of thioacetic acid is refluxed for 2 hours while irradiating with ultraviolet light and then allowed to stand overnight. The mixture is concentrated in vacuo to one-half volume, cooled and the residue collected, dissolved in acetone, filtered and the acetone evaporated. The residue is dissolved in 50 parts by volume of benzene and chromatographed on 200 parts by weight of silica gel. The column is eluted with 5000 parts by volume of 5% ethyl acetate in benzene followed by 1500 parts by volume of ethyl acetate in benzene.
  • Example 5 A mixture of one part by weight of ZI-hYdl'OXY-lapropionlythio-4-pregnene-3,20-dione, 4 parts by volume of isobutyric anhydride and 8 parts by volume of pyridine is warmed on the steam bath until homogeneous. The solution is allowed to stand overnight, diluted with water and extracted with methylene chloride. The methylene chloride solution is washed with sodium carbonate solution and concentrated in vacuo. The residue is dissolved in 50 parts by volume of benzene and chromatographed on silica gel.
  • the chromatographic column is washed with 2000 parts by volume of benzene and eluted with 3000 parts by volume of 5% ethyl acetate in benzene.
  • the solvents are removed from the eluate leaving 21 isobutyroxy 1a propionylthio 4 pregnene 3,20- dione which exhibits a maximum in the ultraviolet absorption spectrum at 241 millimicrons and absorption maxima in the infrared at .5.7, 5.8, 5.95, 6.2 and 10.7 microns.
  • Example 6 A mixture of 1.5 parts by weight of 21-hydroxy-L4- pregnadiene-3,20-dione and 1.5 :partsby volume'of thiopropionic acid is heated for 20 minutes on the steam bath. Then 10 parts by volume of benzene is added and the solution chromatographedon parts by weight of silica gel. The chromatographic column is washed with 2000 parts by volume of benzene and eluted with 5000 parts by volume of 5% ethyl acetate in benzene.
  • the solvents are removed from the eluate in vacuo to yield 21-propionoxy-1a-propionylthio-4-pregnene-3,20-dione as a glass which exhibits maxima in the ultraviolet spectrum at 240 millimicrons and in the infrared absorption spectrum at 5.71, 5.78, 5.95, 6.19, 6.82, 7.03, 7.25, 7.84, 8.5, 9.17, 9.8 and 10.7 microns.
  • the chromatographic column is eluted a second time with 4000 parts by volume of 15% ethyl acetate in benzene, the solvents are removed from the eluate in vacuo to yield 21-hydroxy-1a-propionylthio-4-pregnene-3,20- dione which melts at 161 and exhibits maxima in the ultraviolet absorption spectrum at 241 millimicrons and in the infrared absorption spectrum at 2.82, 5.95, 6.18, 6.85, 7.02, 7.18, 7.39, 7.82, 8.20, 9.17, 9.36, 9.8 and 10.7 microns.
  • R is the (lower) alkanoyl radical
  • R is a. member of the group of radicals consisting of acetyl, hydroxyacetyl and (lower) alkanoyloxyacetyl
  • X is a member of the group of radicals consisting of hydrogen and hydroxyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

United States Patent 2,904,561 1-ACYLTHIO-4-PREGNENE-3,20-DIONES Raymond M. Dodson, Park Ridge, and Robert C. Tweit, Wilmette, Ill., assignors to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Application May 2, 1958 Serial No. 732,454
4 Claims. (Cl. 260-4973) The present invention is concerned with lot-acylthio substitution products of 4-pregene-3,20-diones. The compositions of this invention can be represented by the general structural formula wherein R is a (lower) alkanoyl radical, R is amember of the group of radicals consisting of acetyl, hydroxyacetyl and (lower) alkanoyloxyacetyl and X is a member whereinR" represents hydrogen or a lower alkyl radical, to a l,4-pregnadiene-3,20-dione which has the structural formula wherein R and X have the means as aforesaid. The addition reaction to the 1,2-double bond proceeds fairly rapidly at elevated temperatures, such as those in excess of 50, and can be carried out optionally under the influence of ultraviolet light. In carrying out the addition reaction with lower boiling thioalkanoic acids, such as thioacetic acid, it is convenient to conduct the reaction at the reflux temperature of the reaction mixture; whereas with higher boiling thioalkanoic acids it is convenient to conduct the reaction at a temperature of about 90-400". Heating periods of up to a few hours are sufficient to achieve substantial conversion to the desired reaction products. Typically, the desired compound is obtained in a satisfactory state of purity by direct filtration of the cooled reaction mixture, preceded, where necessary, by removal of excess thioalkanoic acid. If desired, however, the reaction product can 2,904,561 Patented Sept. 15, 1959 be purified by chromatographic techniques using adsorbents such as silica gel followed by elution with mixtures of ethyl acetate and benzene.
When the compound desired is one having an esterified hydroxyl group at position 21, it is suitable to employ as starting material the corresponding 21-ester of a 2l-hydroxy-1,4-pregnadiene-3,ZO-dione; or alternatively, to carry out the addition reaction on the derivative having a free 21-hydroxyl group, and subsequently to complete the partial acylation effected by the thioalkanoic acid by adding pyridine and a lowar alkanoic acid anhydride of the same kind to the reaction mixture prior to the isolation of the product.
When the final product desired is one having a free ZI-hydroxyl group, it can be obtained by the treatment of the corresponding Zl-hydroxy-l,4-pregnadiene-3,20- dione, suitably in an inert solvent, with only one molecular equivalent of the thioalkanoic acid. It can be obtained also by treating the free 21-hydroxy-1,4-pregnadiene derivative with an excess of the thioalkanoic acid, but under milder conditions, such as by the use of a shorter reaction time. The quantity of 21-ester which does form by the acylating action of the thioalkanoic acid is then removed by chromatography.
The addition of thioalkanoic acids to the 1,2-double bond of the starting materials employed in the practice of this invention proceeds under steric influences such that of the stereoisomers formed, one is obtained in predominant amount. The isomer obtained in predominant amount has in each case been characterized herein as possessing the oc-COnfigulfltlOll of the l-acylthio group. This configuration has been designated in order to provide a more complete exposition of the present invention, and in order that the specification shall constitute a more useful contribution to the art. However, the designated configuration of the l-acylthio group is based upon an analysis of the molecular rotation data presently appearing in the chemical literature, and is therefore not to 'be interpreted except in relation tothe state of the art presently known to organic chemists. It will be apparent that no part of the specification will be materially defective if it should be established later that the configuration is the opposite of that deducible from data presently available to workers in the field.
The compounds of the invention have useful pharmacological properties. They are hormonal agents of the luteoid and adrenocorticoid types, more specifically progestational agents and anti-inflammatory and neoglycogenet-ic agents of the cortisone type.
This invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and in methods will be apparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees centigrade C.) and quantities of materials are expressed in parts by weight and parts by volume which bear the same relation one to the other as kilograms to liters.
Example 1 A mixture of 2.0 parts by weight of l-dehydroprogesterone and 1 part by volume of thioacetic acid is heated and irradiated with ultraviolet light for one and one-half hours. To the mixture is added 10 parts by volume of benzene and the resulting solution concentrated under vacuum. The residue is stirred with ether and the solid which forms is collected and washed with a little ether to yield 1oz-acetylthioprogesterone; melting point 147.5- 149"; specific rotation +212.5 (chloroform); ultraviolet maximum at 241 m l with extinction coeflicient 16,300.
3 Example 2 A solution of 2.82 parts by weight of 21-acetoxy-17ahydroxy-l,4-pregnadiene-3,20-dione and 2 parts by volume of thioacetic acid is heated and irradiated with ultraviolet light. The reaction mixture is concentrated to onehalf volume in vacuo, cooled and diluted with ether. The solid precipitate which forms is collected and recrystallized from acetone to yield ZI-acetoxy-la-acetylthio- 17 a-hydroxy-4-pregnene-3,20-dione; melting point 202- 204 (dec.); specific rotation +149.5 (chloroform).
Example 3 A mixture of 0.65 part by weight of 17a,21-dihydroxy- 1,4-pregnadiene-3,11,20-trione ZI-ethylcarbonate and 0.6 part by volume of thioacetic acid is refluxed for 3 hours while irradiating with ultraviolet light. On standing overnight a solid residue forms. Part of the excess thioacetic acid is removed under vacuo and the solid residue is collected, washed with ether and crystallized twice from acetone to yield 1a-acetylthio-2l-ethylcarbonyldioxy-17ahydroxy-4-pregnene-3,l1,20-trione; melting point 202.5 205 (dec.); specific rotation +174 (chloroform).
Example 4 A mixture of 4.49 parts by weight of 21-acetoxy-l,4- pregnadiene-3,20-dione and 3 parts by volume of thioacetic acid is refluxed for 2 hours while irradiating with ultraviolet light and then allowed to stand overnight. The mixture is concentrated in vacuo to one-half volume, cooled and the residue collected, dissolved in acetone, filtered and the acetone evaporated. The residue is dissolved in 50 parts by volume of benzene and chromatographed on 200 parts by weight of silica gel. The column is eluted with 5000 parts by volume of 5% ethyl acetate in benzene followed by 1500 parts by volume of ethyl acetate in benzene. The eluates are combined, the solvent removed and the residue crystallized from methylene chloride-ether to yield 21-acetoxy-1a-acetylthio-4-pregnene-3,20-dione; melting point 149-150"; specific rotation +193 (chloroform); ultraviolet maximum at 241 m with an extinction coefficient 17,300.
Example 5 A mixture of one part by weight of ZI-hYdl'OXY-lapropionlythio-4-pregnene-3,20-dione, 4 parts by volume of isobutyric anhydride and 8 parts by volume of pyridine is warmed on the steam bath until homogeneous. The solution is allowed to stand overnight, diluted with water and extracted with methylene chloride. The methylene chloride solution is washed with sodium carbonate solution and concentrated in vacuo. The residue is dissolved in 50 parts by volume of benzene and chromatographed on silica gel. The chromatographic column is washed with 2000 parts by volume of benzene and eluted with 3000 parts by volume of 5% ethyl acetate in benzene. The solvents are removed from the eluate leaving 21 isobutyroxy 1a propionylthio 4 pregnene 3,20- dione which exhibits a maximum in the ultraviolet absorption spectrum at 241 millimicrons and absorption maxima in the infrared at .5.7, 5.8, 5.95, 6.2 and 10.7 microns.
Example 6 A mixture of 1.5 parts by weight of 21-hydroxy-L4- pregnadiene-3,20-dione and 1.5 :partsby volume'of thiopropionic acid is heated for 20 minutes on the steam bath. Then 10 parts by volume of benzene is added and the solution chromatographedon parts by weight of silica gel. The chromatographic column is washed with 2000 parts by volume of benzene and eluted with 5000 parts by volume of 5% ethyl acetate in benzene. The solvents are removed from the eluate in vacuo to yield 21-propionoxy-1a-propionylthio-4-pregnene-3,20-dione as a glass which exhibits maxima in the ultraviolet spectrum at 240 millimicrons and in the infrared absorption spectrum at 5.71, 5.78, 5.95, 6.19, 6.82, 7.03, 7.25, 7.84, 8.5, 9.17, 9.8 and 10.7 microns.
The chromatographic column is eluted a second time with 4000 parts by volume of 15% ethyl acetate in benzene, the solvents are removed from the eluate in vacuo to yield 21-hydroxy-1a-propionylthio-4-pregnene-3,20- dione which melts at 161 and exhibits maxima in the ultraviolet absorption spectrum at 241 millimicrons and in the infrared absorption spectrum at 2.82, 5.95, 6.18, 6.85, 7.02, 7.18, 7.39, 7.82, 8.20, 9.17, 9.36, 9.8 and 10.7 microns.
What is claimed is:
1. A compound of the formula wherein R is the (lower) alkanoyl radical, R is a. member of the group of radicals consisting of acetyl, hydroxyacetyl and (lower) alkanoyloxyacetyl and X is a member of the group of radicals consisting of hydrogen and hydroxyl.
2. 1a-acetylthio-4-pregnene-3,20-dione.
3. 1a acetylthio 21 acetoxy 17a hydroxy 4- pregnene-3,20-dione.
4. 1a acetylthio 21 acetoxy 4 pregnene 3,20- dione.
No references cited.

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1. A COMPOUND OF THE FORMULA
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3276982A (en) * 1962-04-03 1966-10-04 Res Inst Medicine Chem Method of generating free acyl radicals by irradiation of acyl derivatives of dithiocarboxylic acids

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* Cited by examiner, † Cited by third party
Title
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3276982A (en) * 1962-04-03 1966-10-04 Res Inst Medicine Chem Method of generating free acyl radicals by irradiation of acyl derivatives of dithiocarboxylic acids

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